Studies into the pathophysiology of schizophrenia have support an association between the dopamine (DA) system and prefrontal cortex (PFC). In particular, postmortem studies of schizophrenia by Project-Lewis have provided evidence suggesting that this disorder may be characterized by a decrease in PFC DA innervation and thalamocortical regulation, which may ultimately impact on the integration of information processing in this region (Project-Cohen). Using in vivo intracellular recordings in a rat model, we will examine factors involved in the regulation of PFC activity, and how the PFC can modulate subcortical DA systems. Furthermore, in collaboration with Project-Zigmond we will examine whether prepubertal disruption of PFC DA inputs alters the regulation of PFC output neurons and their impact on mesolimbic DA systems. This will be done using in vivo intracellular recordings to examine the physiology of deep layer prelimbic PFC neurons in terms of the following: 1) their regulation by prefrontal associational cortical inputs and thalamic afferents, and how this is modulated by DA, 2) their interaction with subcortical DA systems, and 3) the influence of prepubertal versus adult lesions of the prefrontal DA innervation on the regulation of cortical and thalamic inputs to prelimbic output neurons. Each of the studies using prepubertal and adult lesions of the prefrontal DA innervation will be carried out in parallel with the biochemical assessments done by Project-Zigmond. By using an in vivo electrophysiological approach, we hope to derive information that can be integrated with the biophysical studies in primate tissue (Project- Barrionuevo) and that will be relevant to studies of the functional organization of the PFC (Project-Olson) and its involvement in the pathophysiology of schizophrenia.